Synthesis and Characterization of a Novel Thermoresponsive OEGDA‑MAA Nanogel Polymer

Background

Polymers that respond to external triggers such as temperature, pH, or ionic strength are pivotal in actuators, drug delivery, and tissue engineering. Among them, thermoresponsive polymers with a well‑defined VPTT—commonly called LCST polymers—have attracted intense research interest. The prototypical example, poly(N‑isopropylacrylamide) (PNIPAM), shows a VPTT near 32 °C, making it a benchmark for biomedical applications. However, PNIPAM suffers from hysteresis, strong protein adsorption, and hydrolysis products that limit its clinical use.

Polyethylene glycol (PEG)–based polymers offer a non‑toxic, non‑immunogenic alternative. Yet, PEG itself is only thermoresponsive under high temperature or pressure, prompting the design of OEG macromonomers bearing functional groups at one or both termini. These macromonomers are polymerized via anionic, cationic, ATRP, RAFT, or NMP routes, enabling fine control over molecular weight, architecture, and comonomer ratio. Adjusting these parameters tunes the LCST/UCST of OEG polymers, as documented in recent reviews.

Most OEG‑based responsive polymers are comb‑like, with a methacrylate backbone and pendant OEG chains. In contrast, the polymer reported here, P(OEGDA‑MAA), is a cross‑linked network formed by copolymerizing OEG diacrylate (OEGDA) with methacrylic acid (MAA) via precipitation polymerization in water. This architecture yields a distinct LCST in water and UCST in ethanol, offering a new class of stimuli‑responsive materials with potential biomedical relevance.

Methods

Materials

OEGDA (Mn = 575) was sourced from Aladdin (Shanghai, China). MAA, purified by basic Al₂O₃ treatment, was supplied by Tianjin Guangcheng Chemicals. Ammonium persulfate (APS) was purchased from Tianjin Hedong Hongyan Chemicals. Dialysis membranes (MWCO 3500) were from Union Carbide Corporation.

Preparation of P(OEGDA‑MAA)

In a 1 L flask, 0.8166 g OEGDA (1.43 mmol) and 0.1834 g MAA (2.11 mmol) were dissolved in 500 mL deionized water. After nitrogen purging, 10 wt % APS (300 µL) was added. The reaction was sealed and heated to 70 °C for 4 h. Turbidity indicated polymer precipitation. Upon cooling, the turbid emulsion cleared. A 2 M NaCl solution (pH 1.0) was added to induce precipitation, followed by centrifugation (10 000 rpm), redispersion in water, and dialysis for 72 h to remove salt.

Characterization

1H NMR (400 MHz, Bruker) in DMSO‑d₆ confirmed composition. OEGDA content was also quantified by potentiometric titration. VPTT in aqueous (pH 1.0, 150 mM NaCl) and ethanolic dispersions was determined by monitoring 565 nm transmittance while cooling from 70 °C to 10 °C. Dynamic light scattering (DLS, Malvern Nano‑ZS) measured particle size and distribution.

Results and Discussion

Composition Analysis

1H NMR integration of the carboxylic (12.35 ppm) and ester (4.11 ppm) peaks yielded an OEGDA content of 40.9 mol %, matching the feed ratio and confirming complete copolymerization (Eq. 1). Potentiometric titration gave 38.8 mol % OEGDA, corroborating the NMR result.

$$\text{[OEGDA]}(\%) = \frac{S_b/4}{S_a + S_b/4}$$

Morphology

SEM images (Fig. 2) revealed ~40 nm nanogel particles in the dry state from aqueous dispersions. The low‑VPTT dispersion (< 33 °C) appeared transparent, confirming a fully swollen state. DLS measured a hydrodynamic radius of ~12 nm at 70 °C, indicating highly swollen, isolated particles that likely aggregate during drying.

In ethanol, the same polymer formed larger aggregates (Fig. 2b–c) due to interpenetration of hydrophilic chains above the UCST‑type VPTT. At higher ethanol concentrations, continuous hydrogel films emerged.

LCST‑type VPTT in Water

At 1 mg mL⁻¹, the VPTT was 33 °C at pH 1.0, shifting to 42 °C at pH 3 and disappearing entirely at pH 5. The pH dependence arises from protonation of carboxyl groups below pKa 4.8, enabling hydrogen bonding with ether oxygens. At high pH, ionization induces electrostatic repulsion, maintaining a swollen state across the temperature range.

DLS (Fig. 4) showed a gradual size increase from 15 nm (10 °C) to 20 nm (25 °C), followed by an abrupt jump to ~600 nm above the VPTT, indicative of dehydration‑induced aggregation.

UCST‑type VPTT in Ethanol

In ethanol, the polymer remained transparent at 70 °C, but transmittance dropped as temperature decreased. At 1 mg mL⁻¹, the VPTT was 43 °C, with a two‑step transition: initial chain dehydration (size increase to ~7 nm) and subsequent aggregation (size reaching 150 nm at 40 °C, 270 nm at 25 °C). The mechanism mirrors LCST behavior but in reverse temperature direction (Fig. 6).

Phase‑Transition Mechanism

Both LCST and UCST transitions involve a two‑step process: (1) loss of solvent affinity leading to chain collapse, and (2) aggregation of collapsed nanogels. The cross‑linked OEGDA‑MAA network exhibits pronounced concentration dependence—VPTT decreases from 33 °C (1 mg mL⁻¹) to 27 °C (5 mg mL⁻¹)—due to increased probability of interparticle contact.

Conclusions

We have synthesized a cross‑linked OEG‑MAA polymer that displays both LCST‑type VPTT in water (33 °C at 1 mg mL⁻¹, pH 1.0) and UCST‑type VPTT in ethanol (43 °C). The transitions are tunable via concentration and pH, and the particle size evolves predictably across the transitions. These attributes position P(OEGDA‑MAA) as a promising candidate for temperature‑responsive biomedical applications.

Abbreviations

APS:

Ammonium persulfate

ATRP:

Atom transfer radical polymerization

DLS:

Dynamic light scattering

EG:

Ethylene glycol

LCST:

Lower critical solution temperature

MAA:

Methacrylic acid

OEG:

Oligo(ethylene glycol)

OEGDA:

Oligo(ethylene glycol) diacrylate

P(OEGDA‑MAA):

Poly(oligo(ethylene glycol) diacrylate‑methacrylic acid)

PEG:

Poly(ethylene glycol)

PNIPAM:

P(N‑isopropylacrylamide)

POEGMA:

Poly[(oligo(ethylene glycol) methyl ether methacrylate]

RAFT:

Reversible addition‑fragmentation chain transfer polymerization

R_h:

Hydrodynamic particle radius

UCST:

Upper critical solution temperature

VPTT:

Volume phase transition temperature